5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethyl sulfinyl pyrazole or 5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[-(1(R,S)-trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile also known as Fipronil is a novel pesticide characterized by high efficiency, low toxicity and especially low residue.
There are various routes to synthesize Fipronil by oxidation of thiopyrazole with various other oxidizing agents in suitable solvents. Oxidation of sulfides is a very useful route for the preparation of sulfoxides. Literature is replete with the conversion of sulfides to sulfoxides and/or sulfones. However, most of the existing methods use expensive, toxic or rare oxidizing reagents, which are difficult to prepare, are very expensive and cannot be used on commercial scale. Many of these processes suffer from poor selectivity.
WO01/30760 describes oxidation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole with trifluoro-acetic acid and hydrogen peroxide in the presence of boric acid. The quantity of trifluoroacetic acid used is 14.5 molar equivalents. The patent also discloses the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano-4-trifluoromethylthio-pyrazole from 5-amino-1-(2,6-dichloro-4-trifluoromethyl phenyl)-3-cyano pyrazole-4-yl disulphide.
European Patent publication No. 295117 describes the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product.
Oxidizing agents such as perbenzoic acids do not provide effective and regioselective oxidation of electron deficient sulfides such as trifluoromethylsulphides which are less readily oxidized than other sulfides. Trifluoroacetic acid and trichloroacetic acid are found to be very efficient and regioselective oxidation medium for oxidation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-pyrazole in presence of hydrogen peroxide. Trichloroacetic acid can not be used alone due to higher melting point. Trifluoroacetic acid on the other hand is very regioselective with respect to conversion and low by-products formation. However, it is expensive, water miscible, corrosive to metal as well as glass, comparatively lower boiling and it's recovery (in anhydrous form) is complex in nature.
WO00/35851/2000 talks about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro-benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and ammonia in the presence of N-methylpyrrolidone at 250° C. to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5-trichlorobenzotrifluoride in 72% GLC conversions, 3,4-dichloro and tetrachlorobenzotrifluoride. The process to get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious. Moreover in-spite of using very pure intermediates, substantial amount of an undesired isomer (3-amino-4,5-dichlorobenzotrifluoride) is also obtained.
Another approach to generate 3,4,5-trichlorobenzotrifluoride with high yield and purity is to perform denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, the reaction conditions are too drastic to be employed for an industrial process.
The known commercial processes for the manufacture of Fipronil uses corrosive and expensive chemical such as trifluoroaceticacid, hydrogen peroxide and m-chloroperbenzoicacid Trifluoroacetic acid is expensive and generally not used in large quantities, as well as of m-chloroperbenzoic acid is difficult to handle at commercial scale due to its un-stability and detonating effect. Also the raw material used such as 2,6-Dichloro-4-trifluoromethylaniline are not easily available or made. The overall process for the Fipronil as disclosed above is found to be unsatisfactory in one respect or the other.
Thus, there is felt a need for preparing Fipronil from easily available raw materials in a simple and economical manner at an industrial level, with high yields and purity.